A multi-center translational study will be conducted in order to evaluate the ability of a bedside optical technology to monitor neoadjuvant chemotherapy response in breast cancer patients with locally-advanced disease. The technology, Diffuse Optical Spectroscopic Imaging (DOSI), will be combined with MRI and biomarkers that provide anatomic and molecular correlates, respectively. The proposed studies build on the infrastructure established by the NCI Network for Translational Research in Optical Imaging (NTROI), which has allowed us to validate and standardize DOSI-MRI co-registration methods, data analysis, histopathology, and protocol design. Five clinical sites with identical DOSI instruments and MRI protocols will participate: University of California, Irvine, University of California, San Francisco, University of Pennsylvania, Dartmouth, and Harvard/MGH. A 6th site, Siemens Corporate Research, will provide data and informatics support using specially developed software. The proposed NTR will be integrated into 2 well-established NCI programs supported by ACRIN and I-SPY in order to leverage DOSI with standard MRI and tissue biomarker protocols. Developmental studies will explore blood biomarkers, as well as social and economic factors affecting the acceptance of DOSI for breast cancer chemotherapy management. The resulting NTR-ACRIN-ISPY partnership will facilitate the first multi-center, multi-modality study designed to validate the role of optics in monitoring and predicting response to cancer chemotherapies. Our long-term goal is to provide oncologists with quantitative, non-invasive, standardized optical endpoints that can be used to rapidly optimize therapy for individual breast cancer patients.